This research will continue our effort to develop small molecules to target the wild-type and drug-resistant HIV proteases. In addition, we will identify conserved HIV RNA sequences essential for the translation of the protease and develop small molecules to target such sequences. The ultimate goal is to develop new small molecule therapy to tackle the problem of drug resistance in HIV infection. The specific aims include: 1. Develop new generation HIV protease inhibitors based on the proteases of resistant strains developed against TL-3 and existing inhibitors in the clinic. 2. Define the specificity, especially of P1 -P3 groups in drug-resistant HIV proteases. 3. Identify conserved RNA sequences in the untranslational and the protease- translational domains targets for drug discovery. 4. Develop small molecule arrays for use to identify new drug candidates to target such RNA sequences.